Kaposi's syndrome (KS) is a multifocal vascular tumor of mixed cellular composition that is the most common neoplasm in patients with acquired immunodeficiency syndrome (AIDS). A new member of the herpesvirus group, Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8), has been consistently identified in KS body cavity- based lymphoma and some forms of Castleman's disease. Although still limited, the presently available data provide compelling evidence that KSHV is the long-sought infectious cause of KS. The proposed research is directed toward investigating modulation of cellular signaling by a newly identified KSHV K15 - At a position equivalent to the gene encoding the LMP2A of Epstein Barr virus (EBV), KSHV contains a distinct open reading frame called K15. Although K15 does not exhibit homology to LMP2A, both proteins contain similar structural organization including multiple transmembrane spanning domains and signal transducing modules. We hypothesize that K15 modulates cellular signal transducing activity to that K15 alters cellular signal transducing activity to regulate viral lytic reactivation and to contribute to deregulation of cell growth control. Initial research will focus on the characterization of expression of K15 gene in various KSHV infected cells and tumor tissues. Detailed biochemical studies on the role of K15 will include mutational analysis, effect on cellular signal transduction, and identification of cellular partners. To define the role of K15 in viral lytic reactivation and transformation, we propose to test whether K15 is capable of substituting for the LMP2A function in EBV LMP2A- lymphoblastoid cell lines (LCLs) and for the Tip function in context of herpesvirus saimiri. The proposed studies will increase our understanding of molecular mechanism of the KSHV latency and pathogenesis.